In the United States, as many as one couple in five seeks infertility treatment, with male infertility being the leading cause of half the cases reportd. Understanding the molecular basis for infertility remains a major goal in the search for effective fertility treatments and options. An emerging theory identifies low zinc concentration in seminal plasma as a potential physical source of male infertility; however, the role of intracellular zinc has not yet been identified. The O'Halloran and Woodruff labs recently discovered that spermatozoa accumulate 35 million total zinc atoms to the sperm head and midpiece during capacitation while labile zinc decreases approximately 50% during the first 30 minutes of capacitation. We hypothesize that fluctuations in intracellular zinc concentrations that occur during sperm activation are essential in promoting chromatin compaction and activating protease activity during capacitation. The goal of this fellowship research project is to elucidate the role and mechanism of zinc signaling during sperm capacitation. This goal will be achieved using a combination of physical science, chemistry, and molecular biology approaches. This proposal will determine (a) if the zinc uptake observed during capacitation is essential for activation success; and (b) the molecular mechanism of zinc action during activation on metalloproteins, protease activity, and chromatin compaction. The outcome of this research will provide new insights into zinc signaling in spermatozoa that will aid in the understanding and development of treatment options for male infertility. In addition to an interdisciplinary research program supported by dual mentors in chemistry and reproductive science, this fellowship will provide an opportunity for transdisciplinary training and career development activities. These will include participation in a broad range of professional meetings, new training in teaching methods, and participation in communications skills workshops and grant writing seminars sponsored by The Graduate School at Northwestern. In addition, fellowship support will enable attendance at professional development events outside of Northwestern University, including national academic conferences and laboratory workshops, such as Frontiers in Reproduction at Woods Hole. This fellowship training will enable the applicant to excel professionally and academically at the chemistry:biology interface. In addition, this fellowship will foster an acquisition of the knowledge and professional skills necessary for a successful transition to a post-doctoral fellow position and ultimately as an independent transdisciplinary researcher.